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Epithelial Plasticity in Cancer: Unmasking a MicroRNA Network for TGF-β-, Notch-, and Wnt-Mediated EMT.

Zoni E, van der Pluijm G, Gray PC, Kruithof-de Julio M - J Oncol (2015)

Bottom Line: Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT.In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways.Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

ABSTRACT
Epithelial-to-mesenchymal transition (EMT) is a reversible process by which cancer cells can switch from a sessile epithelial phenotype to an invasive mesenchymal state. EMT enables tumor cells to become invasive, intravasate, survive in the circulation, extravasate, and colonize distant sites. Paracrine heterotypic stroma-derived signals as well as paracrine homotypic or autocrine signals can mediate oncogenic EMT and contribute to the acquisition of stem/progenitor cell properties, expansion of cancer stem cells, development of therapy resistance, and often lethal metastatic disease. EMT is regulated by a variety of stimuli that trigger specific intracellular signalling pathways. Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT. In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways. Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

No MeSH data available.


Related in: MedlinePlus

Interaction between miRs from the 30-miR signature and their predicted target genes overlaid on KEGG TGF-β, Notch, and Wnt pathways.
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fig3: Interaction between miRs from the 30-miR signature and their predicted target genes overlaid on KEGG TGF-β, Notch, and Wnt pathways.

Mentions: Interestingly, we have identified interactions between RHOA and a group of 5 validated miRs (miR-155, miR-124, miR-375, miR-122, and miR-31) [12–17] (Figure 3). More specifically, in endothelial cells, miR-155 was shown to block the acquisition of the mesenchymal phenotype induced by TGF-β by directly targeting RHOA [17]. Similar observations were made in osteoclast precursor cells, where overexpression of miR-124 decreased RHOA expression and reduced cell migration [18]. miR-375 also interferes with cytoskeletal organization by indirectly targeting RHOA during neuronal development [12]. Dramatic effects on migration and cytoskeleton disruption have also been reported for miR-122 in hepatocellular carcinoma (HCC). In this context, miR-122 and RHOA interact directly and overexpression of RHOA reverts miR-122-induced mesenchymal-to-epithelial transition (MET) and inhibition of migration [16]. Finally, in breast cancer cells it was demonstrated that overexpression of miR-31 decreases invasion and metastasis via downregulation of RHOA [15] (Figure 3). Together, these findings highlight the relevance of these miRs in interfering with RHOA mediated EMT.


Epithelial Plasticity in Cancer: Unmasking a MicroRNA Network for TGF-β-, Notch-, and Wnt-Mediated EMT.

Zoni E, van der Pluijm G, Gray PC, Kruithof-de Julio M - J Oncol (2015)

Interaction between miRs from the 30-miR signature and their predicted target genes overlaid on KEGG TGF-β, Notch, and Wnt pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4390187&req=5

fig3: Interaction between miRs from the 30-miR signature and their predicted target genes overlaid on KEGG TGF-β, Notch, and Wnt pathways.
Mentions: Interestingly, we have identified interactions between RHOA and a group of 5 validated miRs (miR-155, miR-124, miR-375, miR-122, and miR-31) [12–17] (Figure 3). More specifically, in endothelial cells, miR-155 was shown to block the acquisition of the mesenchymal phenotype induced by TGF-β by directly targeting RHOA [17]. Similar observations were made in osteoclast precursor cells, where overexpression of miR-124 decreased RHOA expression and reduced cell migration [18]. miR-375 also interferes with cytoskeletal organization by indirectly targeting RHOA during neuronal development [12]. Dramatic effects on migration and cytoskeleton disruption have also been reported for miR-122 in hepatocellular carcinoma (HCC). In this context, miR-122 and RHOA interact directly and overexpression of RHOA reverts miR-122-induced mesenchymal-to-epithelial transition (MET) and inhibition of migration [16]. Finally, in breast cancer cells it was demonstrated that overexpression of miR-31 decreases invasion and metastasis via downregulation of RHOA [15] (Figure 3). Together, these findings highlight the relevance of these miRs in interfering with RHOA mediated EMT.

Bottom Line: Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT.In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways.Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

ABSTRACT
Epithelial-to-mesenchymal transition (EMT) is a reversible process by which cancer cells can switch from a sessile epithelial phenotype to an invasive mesenchymal state. EMT enables tumor cells to become invasive, intravasate, survive in the circulation, extravasate, and colonize distant sites. Paracrine heterotypic stroma-derived signals as well as paracrine homotypic or autocrine signals can mediate oncogenic EMT and contribute to the acquisition of stem/progenitor cell properties, expansion of cancer stem cells, development of therapy resistance, and often lethal metastatic disease. EMT is regulated by a variety of stimuli that trigger specific intracellular signalling pathways. Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT. In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways. Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

No MeSH data available.


Related in: MedlinePlus